第３章第１節の実験

102

103

3-(2-Ethoxy-2-oxoethyl)--[3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-indol-6-yl]-5-methoxy-1H-i ndole-2-butanoic Acid Ethyl Ester (119). Brown oil; IR (neat): 3358, 1724 cm^-1; ¹H NMR (500 MHz, CDCl3) : 8.36 (1H, br s), 8.00 (1H, br s), 7.19 (1H, s), 7.11 (1H, d, J = 9.0 Hz), 7.04-7.02 (3H, m), 6.75 (1H, dd, J = 9.0, 2.5 Hz), 4.66 (1H, t, J = 8.0 Hz), 4.13 (2H, q, J = 7.0 Hz), 4.06 (2H, q, J = 7.0 Hz), 4.05 (2H, q, J = 7.0 Hz), 3.87 (3H, s), 3.83 (3H, s), 3.79 and 3.71 (2H, ABq, J = 15.5 Hz), 3.68 (2H, s), 2.49-2.40 (2H, m), 2.39-2.26 (2H, m), 1.24 (3H, t, J = 7.0 Hz), 1.183 (3H, t, J = 7.0 Hz), 1.175 (3H, t, J = 7.0 Hz); ¹³C NMR (125 MHz, CDCl3) : 173.8, 172.1, 172.0, 154.0, 152.0, 139.3, 131.1, 130.4, 128.9, 126.4, 126.3, 123.6, 111.35, 111.29, 110.9, 108.1, 104.8, 100.8, 100.3, 60.8, 60.6, 60.3, 56.00, 55.95, 37.5, 32.7, 31.6, 30.7, 29.2, 14.3, 14.2 (2C); ESI-HRMS m/z: calcd for C32H38O8N2Na [M + Na]⁺ 601.2520, found 601.2522.

[Table 15, entry 11]. To a solution of 12A (1.0 g, 4.0 mmol) in MeCN (40 mL) was added tBuI (1.43 mL, 12.1 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4

and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) to afford 17A (0.79 g, 85%).

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第１０節 第３章第２節の実験

Reaction of tert-Butyl Iodide in Acetonitrile with Water [Scheme 54]. To a solution of tBuI (37 mg, 0.2 mmol) in MeCN (2 mL) was added H2O (36 μL, 2.0 mmol) at reflux. After being stirred for 1 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by PTLC (CHCl3 : MeOH = 10 : 1) to afford N-(1,1-dimethylethyl)acetamide (121) (8.9 mg, 39%) as white solid. The spectral data were identical with those reported in the literature. ⁵⁵⁾

Reduction of 127 [Scheme 60, eq 1]. To a solution of 127 (35 mg, 0.2 mmol) in MeCN (2 mL) was added tBuI (48 μL, 0.4 mmol) at reflux. After being stirred for 10 min, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (hexane : AcOEt = 1 : 1) to afford diethyl 1,2-hydrazinedicarboxylic acid 1,2-diethyl ester (128) (31.7 mg, 90%) as white solid. The spectral data were identical with those reported in the literature. ⁶⁰⁾

(2E, 4E)-4-(2,2-Dimethylhydrazono)-2-butenoic Acid Ethyl Ester (131) ⁶³⁾ [Scheme 61, eq 1].

To a solution of ethyl trans-4-oxo-2-butanoate (1.0 g, 7.8 mmol) in EtOH (20 mL) were added N,N-dimethylhydrazine (0.65 mL, 8.6 mmol) and AcOH (2 drops) at 0 °C. After being stirred for 1 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) to afford 131 (1.26 g, 95%) as yellow oil. IR (neat): 1703 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.41 (1H, dd, J = 15.5, 9.5 Hz), 6.89 (1H, d, J = 9.5 Hz), 5.83 (1H, d, J = 15.5 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.04 (6H, s), 1.29 (3H, t, J = 7.0 Hz);

13C NMR (75 MHz, CDCl3) : 167.1, 143.1, 128.2, 117.1, 59.7, 42.1, 14.1; ESI-HRMS m/z: calcd for C8H14O2N2Na [M + Na]⁺ 193.0947, found 193.0949.

Reduction of 131 [Scheme 61, eq 2]. To a solution of 131 (34 mg, 0.2 mmol) in MeCN (2 mL) was added tBuI (48 μL, 0.4 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (hexane : AcOEt = 2 : 1) to afford 133 (13.7 mg, 40%).

(4E)-4-(Dimethylhydrazono)-butanoic Acid Ethyl Ester (133). Yellow oil; IR (neat): 1735 cm^-1;

1H NMR (300 MHz, CDCl3) : 6.67 (1H, br t, J = 4.0 Hz), 4.14 (2H, q, J = 7.0 Hz), 2.73 (6H, s), 2.58-2.49 (4H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 173.1, 136.1, 60.3, 43.2, 32.0, 28.1, 14.2; ESI-HRMS m/z: calcd for C8H17O2N2 [M + H]⁺ 173.1285, found 173.1285.

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第１１節 第３章第３節第１項の実験

Preparation of Conjugated Hydrazones 12J-M [Table 16]. According to the general procedure A or B described in Table 12, 12J-M was obtained in the yields shown in Table 16.

(2E, 4E)-4-[2-(4-Bromophenyl)hydrazono]-2-butenoic Acid Ethyl Ester (12J). Yellow solid;

Mp: 137-138 °C (hexane-AcOEt); IR (KBr): 3259, 1682 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.91 (1H, br s), 7.49-7.40 (2H, m), 7.36 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz), 6.03-5.94 (1H, m), 4.23 (2H, q, J = 7.0 Hz), 1.31 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 166.7, 142.3, 141.0, 136.2, 132.2, 121.9, 114.7, 113.3, 60.6, 14.2; ESI-HRMS m/z: calcd for C12H14O2N2

79Br [M + H]⁺ 297.0233, found 297.0235.

(2E, 4E)-4-[2-(4-Cyanophenyl)hydrazono]-2-butenoic Acid Ethyl Ester (12K). Yellow solid;

Mp: 174-176 °C (hexane-AcOEt); IR (KBr): 3259, 2216, 1682 cm^-1; ¹H NMR (300 MHz, CDCl3) :

8.33 (1H, br s), 7.57-7.52 (3H, m), 7.44 (1H, dd, J = 15.5, 9.5 Hz), 7.12 (2H, d, J = 8.5 Hz), 6.07 (1H, d, J = 15.5 Hz), 4.25 (2H, q, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3)

: 166.4, 146.6, 140.4, 138.5, 133.7, 123.9, 119.6, 113.2, 103.3, 60.7, 14.2; ESI-HRMS m/z: calcd for C13H14O2N3 [M + H]⁺ 244.1081, found 244.1079.

(2E, 4E)-4-[2-(2-Methylphenyl)hydrazono]-2-butenoic Acid Ethyl Ester (12L). Yellow solid;

Mp: 96-97 °C (hexane-AcOEt); IR (KBr): 3306, 1686 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.86 (1H, br s), 7.57-7.45 (3H, m), 7.21 (1H, t, J = 7.5 Hz), 7.10 (1H, d, J = 7.5 Hz), 6.87 (1H, td, J = 7.5, 1.0 Hz), 6.05-5.94 (1H, m), 4.24 (2H, q, J = 7.0 Hz), 2.23 (3H, s), 1.32 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 166.7, 141.3, 141.0, 136.3, 130.5, 127.3, 121.3, 120.9, 120.7, 113.1, 60.4, 16.9, 14.2; ESI-HRMS m/z: calcd for C13H17O2N2 [M + H]⁺ 233.1285, found 233.1286.

(2E, 4E)-4-[2-(3-Methylphenyl)hydrazono]-2-butenoic Acid Ethyl Ester (12M). Yellow solid;

Mp: 124-125 °C (hexane-AcOEt); IR (KBr): 3280, 1686 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.94 (1H, br s), 7.49 (1H, dd, J = 15.0, 9.5 Hz), 7.41 (1H, dd, J = 9.5, 1.0 Hz), 7.16 (1H, t, J = 7.5 Hz), 6.93 (1H, s), 6.84 (1H, d, J = 7.5 Hz), 6.75 (1H, d, J = 7.5 Hz), 5.97 (1H, d, J = 15.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 2.33 (3H, s), 1.32 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 166.9, 143.1, 141.5, 139.3, 135.3, 129.1, 122.1, 120.7, 113.7, 110.3, 60.4, 21.5, 14.2; ESI-HRMS m/z: calcd for C13H17O2N2 [M + H]⁺ 233.1285, found 233.1284.

106

General Procedure for Reductive Fischer Indolization of Conjugated Hydrazones [Scheme 64].

To a solution of 12B-H, J-N (0.2 mmol) in MeCN (2 mL) was added tBuI (71 μL, 0.6 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (hexane : AcOEt = 3 : 1) to afford 17B-H, J-N in the yields shown in scheme 64.

5-(Phenylmethoxy)-1H-indole-3-acetic Acid Ethyl Ester (17B) ⁶⁸⁾. Yellow oil; IR (neat): 3409, 1727 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.99 (1H, br s), 7.50-7.46 (2H, m), 7.42-7.29 (3H, m), 7.25 (1H, dd, J = 9.5, 0.5 Hz), 7.19-7.15 (2H, m), 6.94 (1H, dd, J = 9.0, 2.5 Hz), 5.11 (2H, s), 4.15 (2H, q, J = 7.0 Hz), 3.72 (2H, d, J = 1.0 Hz), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3)

: 172.1, 153.3, 137.6, 131.4, 128.5, 127.7, 127.6, 123.9, 113.1, 111.9, 108.2, 102.2, 70.8, 60.8, 31.5, 14.2; ESI-HRMS m/z: calcd for C19H20O3N [M + H]⁺ 310.1438, found 310.1437.

5-(Acetylamino)-1H-indole-3-acetic Acid Ethyl Ester (17C). White solid; Mp: 138-139 °C (MeOH); IR (KBr): 3375, 3302, 1716, 1654 cm^-1; ¹H NMR (300 MHz, CD3OD) : 7.74 (1H, d, J = 1.5 Hz), 7.28 (1H, d, J = 9.0 Hz), 7.19-7.16 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 3.71 (2H, s), 2.12 (3H, s), 1.23 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CD3OD) : 174.3, 171.5, 135.4, 131.4, 128.5, 125.7, 117.3, 112.2, 112.0, 108.8, 61.9, 32.1, 23.6, 14.5; ESI-HRMS m/z: calcd for C14H17O3N2 [M + H]⁺ 261.1234, found 261.1233.

5-(Methylthio)-1H-indole-3-acetic Acid Ethyl Ester (17D). Yellow oil; IR (neat): 3405, 1727 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.22 (1H, br s), 7.61 (1H, s), 7.25-7.18 (2H, m), 7.07 (1H, d, J

= 2.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 3.74 (2H, d, J = 0.5 Hz), 2.51 (3H, s), 1.27 (3H, t, J = 7.0 Hz);

13C NMR (75 MHz, CDCl3) : 172.1, 134.7, 127.8, 127.6, 124.0, 123.9, 119.5, 111.7, 107.9, 60.9, 31.2, 18.7, 14.2; ESI-HRMS m/z: calcd for C13H16O2NS [M + H]⁺ 250.0896, found 250.0897.

5-Methyl-1H-indole-3-acetic Acid Ethyl Ester (17E). Yellow oil; IR (neat): 3409, 1727 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.00 (1H, br s), 7.40 (1H, s), 7.23 (1H, d, J = 8.0 Hz), 7.11 (1H, d, J = 2.5 Hz), 7.02 (1H, dd, J = 8.0, 1.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 3.74 (2H, s), 2.45 (3H, s), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.2, 134.4, 128.8, 127.4, 123.7, 123.1, 118.5, 110.8, 108.0, 60.7, 31.4, 21.5, 14.2; ESI-HRMS m/z: calcd for C13H16O2N [M + H]⁺ 218.1176, found 218.1176.

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5-(1,1-Dimethylethyl)-1H-indole-3-acetic Acid Ethyl Ester (17F). Yellow oil; IR (neat): 3409, 1725 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.00 (1H, br s), 7.61 (1H, d, J = 0.5 Hz), 7.29 (2H, d, J = 1.5 Hz), 7.14 (1H, d, J = 2.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 3.77 (2H, d, J = 1.0 Hz), 1.39 (9H, s), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.2, 142.4, 134.1, 126.9, 123.1, 120.5, 114.5, 110.6, 108.4, 60.7, 34.6, 31.9, 31.5, 14.2; ESI-HRMS m/z: calcd for C16H22O2N [M + H]⁺ 260.1645, found 260.1647.

1H-Indole-3-acetic Acid Ethyl Ester (17G) ⁶⁴⁾. Yellow oil; IR (neat): 3409, 1725 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.13 (1H, br s), 7.64-7.60 (1H, m), 7.31 (1H, d, J = 8.0 Hz), 7.22-7.10 (3H, m), 4.16 (2H, q, J = 7.0 Hz), 3.76 (2H, d, J = 0.5 Hz), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.2, 136.0, 127.1, 123.1, 122.0, 119.5, 118.8, 111.2, 108.3, 60.8, 31.4, 14.2;

ESI-HRMS m/z: calcd for C12H14O2N [M + H]⁺ 204.1019, found 204.1022.

5-Fluoro-1H-indole-3-acetic Acid Ethyl Ester (17H) ⁶⁵⁾. Orange oil; IR (neat): 3366, 1723 cm^-1;

1H NMR (300 MHz, CDCl3) : 8.15 (1H, br s), 7.28-7.22 (2H, m), 7.18 (1H, d, J = 2.5 Hz), 6.94 (1H, td, J = 9.0, 2.5 Hz), 4.18 (2H, q, J = 7.0 Hz), 3.72 (2H, d, J = 1.0 Hz), 1.27 (3H, t, J = 7.0 Hz);

13C NMR (75 MHz, CDCl3) : 171.9, 157.9 (d, J = 232.0 Hz), 132.6, 127.6 (d, J = 10.5 Hz), 124.8, 111.8 (d, J = 9.5 Hz), 110.6 (d, J = 26.5 Hz), 108.7 (d, J = 4.5 Hz), 103.9 (d, J = 23.5 Hz), 60.9, 31.3, 14.2; ESI-HRMS m/z: calcd for C12H13O2NF [M + H]⁺ 222.0925, found 222.0926.

5-Bromo-1H-indole-3-acetic Acid Ethyl Ester (17J) ⁶⁶⁾.Yellow oil; IR (neat): 3366, 1725 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.21 (1H, br s), 7.74 (1H, d, J = 2.0 Hz), 7.26 (1H, dd, J = 8.5, 2.0 Hz), 7.17 (1H, d, J = 8.5 Hz), 7.12 (1H, d, J = 2.5 Hz), 4.18 (2H, q, J = 7.0 Hz), 3.71 (2H, s), 1.28 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 171.9, 134.7, 128.9, 125.0, 124.3, 121.5, 112.9, 112.6, 108.1, 61.0, 31.2, 14.2; ESI-HRMS m/z: calcd for C12H13O2N⁷⁹Br [M + H]⁺ 282.0124, found 282.0126.

7-Methyl-1H-indole-3-acetic Acid Ethyl Ester (17L). Colorless oil; IR (neat): 3414, 1727 cm^-1;

1H NMR (300 MHz, CDCl3) : 8.02 (1H, br s), 7.48 (1H, d, J = 8.0 Hz), 7.18 (1H, d, J = 2.5 Hz), 7.09-6.99 (2H, m), 4.16 (2H, q, J = 7.0 Hz), 3.77 (2H, d, J = 0.5 Hz), 2.47 (3H, s), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.1, 135.6, 126.7, 122.70, 122.66, 120.3, 119.8, 116.6, 109.0, 60.8, 31.5, 16.5, 14.2; ESI-HRMS m/z: calcd for C13H16O2N [M + H]⁺ 218.1176, found 218.1176.

108

4-Methyl-1H-indole-3-acetic Acid Ethyl Ester (17M). Colorless oil; IR (neat): 3405, 1727 cm^-1;

1H NMR (300 MHz, CDCl3) : 8.06 (1H, br s), 7.19 (1H, d, J = 8.0 Hz), 7.11 (1H, d, J = 2.5 Hz), 7.06 (1H, dd, J = 8.0, 7.0 Hz), 6.84 (1H, d, J = 7.0 Hz), 4.18 (2H, q, J = 7.0 Hz), 3.92 (2H, d, J = 1.0 Hz), 2.67 (3H, s), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.7, 136.6, 130.5, 125.7, 123.5, 122.2, 121.3, 109.2, 60.8, 33.0, 20.0, 14.2; ESI-HRMS m/z: calcd for C13H16O2N [M + H]⁺ 218.1176, found 218.1174.

6-Methyl-1H-indole-3-acetic Acid Ethyl Ester (17M’). Colorless oil; IR (neat): 3405, 1729 cm^-1;

1H NMR (300 MHz, CDCl3) : 7.94 (1H, br s), 7.50 (1H, d, J = 8.5 Hz), 7.15 (1H, s), 7.10 (1H, d, J

= 2.0 Hz), 6.97 (1H, d, J = 8.5 Hz), 4.16 (2H, q, J = 7.0 Hz), 3.74 (2H, d, J = 1.0 Hz), 2.46 (3H, s), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.1, 136.5, 132.0, 125.1, 122.3, 121.4, 118.6, 111.0, 108.5, 60.7, 31.5, 21.7, 14.2; ESI-HRMS m/z: calcd for C13H16O2N [M + H]⁺ 218.1176, found 218.1175.

1H-Benz[g]indole-3-acetic Acid Ethyl Ester (17N). Green solid; Mp: 105-107 °C (hexane-AcOEt); IR (KBr): 3343, 1718 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.90 (1H, br s), 7.94-7.89 (2H, m), 7.70 (1H, d, J = 9.0 Hz), 7.53-7.38 (3H, m), 7.12 (1H, d, J = 2.5 Hz), 4.19 (2H, q, J = 7.0 Hz), 3.82 (2H, d, J = 0.5 Hz), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.3, 130.7, 130.4, 128.8, 125.4, 123.9, 123.0, 121.7, 121.2, 120.5, 119.4, 118.8, 110.1, 60.9, 31.5, 14.2;

ESI-HRMS m/z: calcd for C16H16O2N [M + H]⁺ 254.1176, found 254.1175.

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第１２節 第３章第３節第２項の実験

(2E, 4E)-4-[2-(4-Methoxyphenyl)-2-methylhydrazono]-2-butenoic Acid Ethyl Ester (23Aa) [Table 17, entry 1]. To a solution of 12A (500 mg, 2.0 mmol) in dry THF (8 mL) was added sodium hydride (100 mg, 2.4 mmol) and the mixture was stirred at 0 °C for 10 min. Then, methyl iodide (0.19 mL, 3.0 mmol) was added to the reaction mixture and the mixture was stirred at reflux.

After being stirred for 1 h, the reaction mixture was diluted with H2O and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was recrystallized from AcOEt/hexane to afford 23Aa (522 mg, 98%) as yellow solid. Mp: 105-106 °C (hexane-AcOEt); IR (KBr): 1710 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.54 (1H, dd, J = 15.5, 9.5 Hz), 7.23 (2H, d, J = 9.0 Hz), 7.18 (1H, d, J = 9.5 Hz), 6.88 (2H, d, J = 9.0 Hz), 5.96 (1H, d, J = 15.5 Hz), 4.23 (2H, q, J = 7.0 Hz), 3.80 (3H, s), 3.36 (3H, s), 1.31 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 167.2, 155.3, 143.1, 141.0, 129.7, 119.1, 117.9, 114.3, 60.2, 55.5, 34.6, 14.3; ESI-HRMS m/z: calcd for C14H19O3N2 [M + H]⁺ 263.1390, found 263.1393.

(2E, 4E)-4-[2-(4-Methoxyphenyl)-2-(phenylmethyl)hydrazono]-2-butenoic Acid Ethyl Ester (23Ab) [Table 17, entry 2]. To a solution of 12A (1.0 g, 4.0 mmol) in dry THF (40 mL) was added sodium hydride (193 mg, 4.8 mmol) and the mixture was stirred at 0 °C for 30 min. Then, benzyl bromide (0.68 mL, 6.0 mmol) was added to the reaction mixture and the mixture was stirred at room temperature. After being stirred for 1.5 h, the reaction mixture was diluted with H2O and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 5 : 1) to afford 23Ab (746 mg, 55%) as yellow solid. Mp:

77-79 °C (hexane-AcOEt); IR (KBr): 1699 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.49 (1H, dd, J = 16.0, 9.5 Hz), 7.37-7.23 (5H, m), 7.16 (2H, d, J = 7.5 Hz), 7.05 (1H, d, J = 9.5 Hz), 6.87 (2H, d, J = 9.5 Hz), 5.79 (1H, d, J = 16.0 Hz), 5.08 (2H, s), 4.19 (2H, q, J = 7.0 Hz), 3.79 (3H, s), 1.28 (3H, t, J

= 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 167.1, 155.5, 142.9, 140.8, 134.8, 130.7, 129.1, 127.5, 126.0, 119.8, 117.8, 114.5, 60.2, 55.6, 52.1, 14.3; ESI-HRMS m/z: calcd for C20H22O3N2Na [M + Na]⁺ 361.1523, found 361.1531.

(2E, 4E)-4-[2-Acetyl-2-(4-methoxyphenyl)hydrazono]-2-butenoic Acid Ethyl Ester (23Ac) [Table 17, entry 3]. To a solution of 12A (1.0 g, 4.0 mmol) in dry THF (20 mL) was added sodium hydride (193 mg, 4.8 mmol) and the mixture was stirred at 0 °C for 30 min. Then, acetic anhydride (0.57 mL, 6.0 mmol) was added to the reaction mixture and the mixture was stirred at reflux. After being stirred for 3.5 h, the reaction mixture was diluted with saturated aqueous NaHCO3 solution

110

and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) to afford 23Ac (901 mg, 78%) as off-white solid. Mp:

123-124 °C (hexane-AcOEt); IR (KBr): 1714, 1699 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.39 (1H, br dd, J = 16.0, 9.5 Hz), 7.06-7.00 (4H, m), 6.99 (1H, d, J = 9.5 Hz), 5.97 (1H, dd, J = 16.0, 0.5 Hz), 4.22 (2H, q, J = 7.0 Hz), 3.86 (3H, s), 2.52 (3H, br s), 1.29 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 173.2, 165.9, 160.1, 140.3, 139.7, 129.8, 127.6, 126.7, 115.5, 60.7, 55.4, 21.9, 14.1;

ESI-HRMS m/z: calcd for C15H19O4N2 [M + H]⁺ 291.1339, found 291.1339.

(2E, 4E)-4-[2-(4-Methoxyphenyl)hydrazono]-4-phenyl-2-butenoic Acid Ethyl Ester (24) [Scheme 65]. According to the general procedure A described in Table 12, 24 was obtained in 79%

yield as yellow solid. Mp: 96-97 °C (hexane-AcOEt); IR (KBr): 3315, 1712 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.71 (1H, br s), 7.70 (1H, d, J = 16.0 Hz), 7.59-7.46 (3H, m), 7.26-7.22 (2H, m), 6.99 (2H, d, J = 9.5 Hz), 6.82 (2H, d, J = 9.5 Hz), 5.50 (1H, d, J = 16.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 3.77 (3H, s), 1.28 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 167.0, 154.5, 144.8, 142.5, 136.9, 130.5, 129.7, 129.4, 128.7, 118.8, 114.45, 114.39, 60.1, 55.4, 14.2; ESI-HRMS m/z: calcd for C19H21O3N2 [M + H]⁺ 325.1547, found 325.1544.

Preparation of Conjugated Hydrazones 25a-d [Table 18]. To a mixture of (2E)-4-oxo-2-butenoic acid ethyl ester, acrolein, crotonaldehyde or cinnamaldehyde (7.8 mmol) and sodium acetate (8.2-9.4 mmol) in EtOH (20 mL) was added N-arylhydrazine hydrochloride (8.2 mmol) at room temperature. After being stirred for 0.5-1 h, the reaction mixture was concentrated under reduced pressure, diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) or recrystallization (AcOEt/hexane) to afford 25a-d in the yields shown in Table 18.

(2E, 4E)-4-(2,2-Diphenylhydrazono)-2-butenoic Acid Ethyl Ester (25a) [entry 1]. Light green solid; Mp: 156-157 °C (hexane-AcOEt); IR (KBr): 1699 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.54 (1H, dd, J = 16.0, 9.5 Hz), 7.45-7.39 (4H, m), 7.26-7.20 (2H, m), 7.16-7.13 (4H, m), 6.90 (1H, d, J

= 9.5 Hz), 5.79 (1H, d, J = 16.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 166.7, 142.6, 142.1, 133.9, 129.8, 125.3, 122.3, 121.3, 60.2, 14.2; ESI-HRMS m/z: calcd for C18H19O2N2 [M + H]⁺ 295.1441, found 295.1439.

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(1E)-2-Propenal N,N-Diphenylhydrazone (25b) [entry 2]. Yellow solid; Mp: 57-58 °C (hexane-AcOEt); IR (KBr): 3067, 1591, 1495, 1290, 1220, 1175, 1096 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.42-7.36 (4H, m), 7.20-7.10 (6H, m), 6.89 (1H, d, J = 9.5 Hz), 6.63 (1H, ddd, J = 17.5, 10.5, 9.5 Hz), 5.32-5.16 (2H, m); ¹³C NMR (75 MHz, CDCl3) : 143.4, 138.2, 135.1, 129.7, 124.4, 122.4, 118.9; ESI-HRMS m/z: calcd for C15H15N2 [M + H]⁺ 223.1230, found 223.1228.

(1E, 2E)-2-Butenal N,N-Diphenylhydrazone (25c) ²⁹⁾ [entry 3]. 25c was obtained as an inseparable 19 : 1 mixture of 2E- and 2Z-isomers. Yellow solid; Mp: 33-35 °C (hexane-AcOEt); IR (KBr): 3025, 1589, 1495, 1292, 1214, 1168, 1058 cm^-1; major isomer: ¹H NMR (300 MHz, CDCl3)

: 7.37 (4H, t, J = 8.0 Hz), 7.17-7.08 (6H, m), 6.87 (1H, d, J = 9.0 Hz), 6.35 (1H, ddd, J = 15.5, 9.0, 2.5 Hz), 5.70 (1H, dq, J = 15.5, 7.0 Hz), 1.80 (3H, dd, J = 7.0, 2.5 Hz); ¹³C NMR (75 MHz, CDCl3)

: 143.8, 138.8, 132.5, 129.8, 129.7, 124.1, 122.4, 18.3; ESI-HRMS m/z: calcd for C16H17N2 [M + H]⁺ 237.1386, found 237.1385.

(1E, 2E)-3-Phenyl-2-propenal N,N-Diphenylhydrazone (25d) ⁷¹⁾ [entry 4]. Yellow solid; Mp:

135-136 °C (hexane-AcOEt); IR (KBr): 3025, 1588, 1557, 1496, 1379, 1218, 1092, 1067 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.44-7.37 (6H, m), 7.34-7.28 (2H, m), 7.25-7.03 (9H, m), 6.54-6.45 (1H, m); ¹³C NMR (75 MHz, CDCl3) : 143.4, 138.2, 136.9, 134.0, 129.8, 128.6, 127.7, 126.8, 126.4, 124.5, 122.4; ESI-HRMS m/z: calcd for C21H19N2 [M + H]⁺ 299.1543, found 299.1543.

Preparation of Conjugated Hydrazones 26a-c [Scheme 66]. To a solution of aryl iodide (5.0 mmol) in DMF (20 mL) were added acrolein diethyl acetal (2.3 mL, 15 mmol), ⁿBu4NOAc (3.0 g, 10.0 mmol), K2CO3 (1.04 g, 7.5 mmol), KCl (0.37 g, 5.0 mmol) and Pd(OAc)2 (30 mg, 0.15 mmol).

The mixture was stirred for 0.5 h at 90 °C. After cooling, 10% HCl was slowly added and the reaction mixture was stirred at room temperature for 10 min. Then, it was diluted with H2O and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The obtained crude product was dissolved in MeOH (30 mL).

To this solution were added N,N-diphenylhydrazine hydrochloride (1.16 g, 5.3 mmol) and sodium acetate (431 mg, 5.3 mmol) at room temperature. After being stirred for 0.5 h, the reaction mixture was concentrated under reduced pressure, diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 5 : 1) to afford 26a-c in the yields shown in Scheme 66.

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(1E, 2E)-3-(4-Methoxyphenyl)-2-propenal N,N-Diphenylhydrazone (26a). Yellow solid; Mp:

157-158 °C (hexane-AcOEt); IR (KBr): 3027, 1598, 1509, 1485, 1254, 1209, 1172, 1094, 1069 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.41 (4H, dd, J = 8.0, 7.5 Hz), 7.34 (2H, d, J = 9.0 Hz), 7.20-7.13 (6H, m), 7.04 (1H, d, J = 9.0 Hz), 6.95 (1H, dd, J = 15.5, 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 6.45 (1H, d, J = 15.5 Hz), 3.81 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 159.3, 143.5, 138.7, 133.8, 129.7, 127.6, 124.7, 124.3, 122.4, 114.0, 55.2; ESI-HRMS m/z: calcd for C22H21ON2 [M + H]⁺ 329.1648, found 329.1645.

(1E, 2E)-3-(4-Cyanophenyl)-2-propenal N,N-Diphenylhydrazone (26b). Yellow solid; Mp:

116-117 °C (hexane-AcOEt); IR (KBr): 3034, 2224, 1600, 1555, 1495, 1372, 1215, 1157, 1095 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.58 (2H, d, J = 8.5 Hz), 7.46-7.39 (6H, m), 7.25-7.13 (7H, m), 7.02 (1H, d, J = 9.0 Hz), 6.46 (1H, d, J = 16.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 143.0, 141.4, 136.6, 132.4, 131.1, 130.5, 129.8, 126.5, 124.9, 122.4, 119.0, 110.3; ESI-HRMS m/z: calcd for C22H18N3 [M + H]⁺ 324.1495, found 324.1491.

(1E, 2E)-3-(2-Thienyl)-2-propenal N,N-Diphenylhydrazone (26c). Yellow solid; Mp: 137-139 °C (hexane-AcOEt); IR (KBr): 3023, 1596, 1558, 1495, 1217, 1092 cm^-1; ¹H NMR (300 MHz, CDCl3)

: 7.44-7.37 (3H, m), 7.21-7.12 (6H, m), 7.00-6.94 (3H, m), 6.88 (1H, dd, J = 15.5, 9.0 Hz), 6.63 (1H, d, J = 15.5 Hz); ¹³C NMR (75 MHz, CDCl3) : 143.3, 142.4, 137.5, 129.7, 127.6, 126.7, 126.3, 126.0, 124.8, 124.5, 122.4; ESI-HRMS m/z: calcd for C19H17N2S [M + H]⁺ 305.1107, found 305.1105.

Reductive Fischer Indolization of 23Aa-Ac [Scheme 67]. According to the general procedure for the reductive Fischer indolization described in Scheme 64, 27Aa-Ac was obtained in the yields shown in Scheme 67.

5-Methoxy-1-methyl-1H-indole-3-acetic Acid Ethyl Ester (27Aa) ^64a).Colorless oil; IR (neat):

1731 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.18 (1H, d, J = 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 7.01 (1H, s), 6.89 (1H, dd, J = 8.5, 2.5 Hz), 4.16 (2H, q, J = 7.0 Hz), 3.86 (3H, s), 3.73 (3H, s), 3.72 (2H, s), 1.27 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.1, 153.8, 132.2, 128.2, 127.9, 112.0, 110.0, 106.3, 100.6, 60.7, 55.8, 32.8, 31.4, 14.2; ESI-HRMS m/z: calcd for C14H18O3N [M + H]⁺ 248.1281, found 248.1283.

5-Methoxy-1-(phenylmethyl)-1H-indole-3-acetic Acid Ethyl Ester (27Ab) ⁶⁸⁾. Orange oil; IR (neat): 1733 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.32-7.24 (3H, m), 7.14-7.07 (5H, m), 6.82 (1H, dd, J = 9.0, 2.5 Hz), 5.24 (2H, s), 4.16 (2H, q, J = 7.0 Hz), 3.85 (3H, s), 3.73 (2H, d, J = 0.5 Hz),

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1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.0, 154.0, 137.5, 131.7, 128.6, 128.2, 127.7, 127.5, 126.7, 112.1, 110.5, 107.0, 100.7, 60.7, 55.7, 50.1, 31.4, 14.2; ESI-HRMS m/z: calcd for C20H21O3NNa [M + H]⁺ 346.1414, found 346.1420.

1-Acetyl-5-methoxy-1H-indole-3-acetic Acid Ethyl Ester (27Ac). White solid; Mp: 89-90 °C (hexane-AcOEt); IR (KBr): 1733, 1695 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.33 (1H, br d, J = 8.5 Hz), 7.43 (1H, br s), 6.98-6.94 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 3.87 (3H, s), 3.69 (2H, d, J = 1.0 Hz), 2.60 (3H, s), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 170.8, 168.1, 156.4, 131.0, 130.4, 124.4, 117.5, 114.8, 113.6, 101.7, 61.1, 55.6, 31.1, 23.7, 14.2; ESI-HRMS m/z: calcd for C15H18O4N [M + H]⁺ 276.1230, found 276.1230.

5-Methoxy-2-phenyl-1H-indole-3-acetic Acid Ethyl Ester (28) [Scheme 68]. According to the general procedure for the reductive Fischer indolization described in Scheme 64, 28 was obtained in 93% yield as colorless oil. IR (neat): 3362, 1724 cm^-1; ¹H NMR (300 MHz, CDCl3) : 8.10 (1H, br s), 7.66-7.62 (2H, m), 7.49-7.43 (2H, m), 7.40-7.34 (1H, m), 7.23 (1H, d, J = 9.0 Hz), 7.13 (1H, d, J

= 2.5 Hz), 6.86 (1H, dd, J = 9.0, 2.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 3.87 (3H, s), 3.79 (2H, s), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 172.3, 154.3, 136.9, 132.4, 130.8, 129.4, 128.9, 128.1, 127.9, 112.7, 111.6, 105.4, 100.9, 60.8, 55.8, 31.2, 14.2; ESI-HRMS m/z: calcd for C19H20O3N [M + H]⁺ 310.1438, found 310.1435.

Reductive Fischer Indolization of 25a-c [Scheme 69]. According to the general procedure for the reductive Fischer indolization of conjugated hydrazones, 29a-c was obtained in the yields shown in Scheme 69.

1-Phenyl-1H-indole-3-acetic Acid Ethyl Ester (29a). Pale yellow oil; IR (neat): 1733 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.69-7.66 (1H, m), 7.57-7.54 (1H, m), 7.53-7.48 (4H, m), 7.34-7.31 (2H, m), 7.26-7.16 (2H, m), 4.19 (2H, q, J = 7.0 Hz), 3.82 (2H, s), 1.28 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 171.8, 139.5, 135.9, 129.5, 128.6, 126.7, 126.3, 124.1, 122.6, 120.2, 119.2, 110.5, 109.5, 60.8, 31.3, 14.2; ESI-HRMS m/z: calcd for C18H18O2N [M + H]⁺ 280.1332, found 280.1333.

3-Methyl-1-phenyl-1H-indole (29b) ⁶⁹⁾.Colorless oil; IR (neat): 3052, 2918, 2862, 1600, 1501, 1456, 1387, 1372 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.64-7.61 (1H, m), 7.58-7.55 (1H, m), 7.52-7.47 (4H, m), 7.35-7.28 (1H, m), 7.25-7.14 (3H, m), 2.39 (3H, d, J = 1.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 139.9, 135.9, 129.7, 129.5, 125.9, 125.4, 124.0, 122.3, 119.7, 119.2, 112.8, 110.3, 9.6; ESI-HRMS m/z: calcd for C15H14N [M + H]⁺ 208.1121, found 208.1120.

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3-Ethyl-1-phenyl-1H-indole (29c) ⁷⁰⁾. Colorless oil; IR (neat): 3052, 2961, 2931, 1598, 1501, 1456, 1379, 1224 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.67-7.64 (1H, m), 7.58-7.55 (1H, m), 7.52-7.45 (4H, m), 7.35-7.27 (1H, m), 7.24-7.13 (3H, m), 2.84 (2H, q, J = 7.5 Hz), 1.38 (3H, t, J = 7.5 Hz);

13C NMR (75 MHz, CDCl3) : 140.0, 136.0, 129.5, 128.9, 125.9, 124.4, 124.0, 122.3, 119.8, 119.7, 119.2, 110.4, 18.2, 14.3; ESI-HRMS m/z: calcd for C16H16N [M + H]⁺ 222.1277, found 222.1277.

1-Phenyl-3-(phenylmethyl)-1H-indole (29d) ⁷¹⁾ [Scheme 69]. To a solution of 25d (60 mg, 0.2 mmol) in MeCN (2 mL) was added tBuI (119 μL, 1.0 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (hexane : AcOEt = 3 : 1) to afford 29d (55.7 mg, 98%) as colorless oil. IR (neat): 3060, 3028, 2905, 1598, 1501, 1456, 1378, 1371 cm^-1; ¹H NMR (300 MHz, CDCl3) :

7.59-7.55 (2H, m), 7.51-7.47 (4H, m), 7.36-7.26 (5H, m), 7.24-7.10 (3H, m), 7.05 (1H, s), 4.16 (2H, s); ¹³C NMR (75 MHz, CDCl3) : 140.8, 139.8, 136.1, 129.5, 128.9, 128.7, 128.4, 126.1, 126.03, 125.96, 124.0, 122.5, 119.9, 119.4, 116.9, 110.5, 31.5; ESI-HRMS m/z: calcd for C21H18N [M + H]⁺ 284.1434, found 284.1435.

Reductive Fischer Indolization of 26a-c [Scheme 69]. To a solution of 26a-c (0.2 mmol) in MeCN (2 mL) was added tBuI (71 μL, 6.0 mmol) at reflux. After being stirred for 3 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (hexane : AcOEt = 3 : 1) to afford 30a-c in the yields shown in Scheme 69.

3-[(4-Methoxyphenyl)methyl]-1-phenyl-1H-indole (30a). Colorless oil; IR (neat): 3056, 2931, 2835, 1598, 1505, 1456, 1373, 1247, 1176, 1036 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.58-7.55 (2H, m), 7.51-7.45 (4H, m), 7.33-7.10 (5H, m), 7.03 (1H, s), 6.84 (2H, d, J = 8.5 Hz), 4.10 (2H, s), 3.78 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 157.8, 139.8, 136.2, 132.8, 129.6, 129.5, 128.8, 126.0, 124.0, 122.4, 119.9, 119.4, 117.4, 113.7, 110.5, 55.2, 30.6; ESI-HRMS m/z: calcd for C22H20ON [M + H]⁺ 314.1539, found 314.1535.

3-[(4-Cyanophenyl)methyl]-1-phenyl-1H-indole (30b). Yellow oil; IR (neat): 3055, 2910, 2228, 1598, 1505, 1457, 1369, 1235, 1136 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.60-7.56 (3H, m), 7.54-7.41 (7H, m), 7.37-7.32 (1H, m), 7.27-7.21 (1H, m), 7.17-7.11 (2H, m), 4.22 (2H, s); ¹³C NMR (75 MHz, CDCl3) : 146.6, 139.5, 136.2, 132.3, 129.6, 129.4, 128.4, 126.4, 126.3, 124.1, 122.8, 120.2, 119.2, 119.1, 114.9, 110.7, 109.9, 31.7; ESI-HRMS m/z: calcd for C22H17N2 [M + H]⁺ 309.1386, found 309.1381.

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1-Phenyl-3-(2-thienylmethyl)-1H-indole (30c). Yellow oil; IR (neat): 3055, 2898, 1598, 1501, 1457, 1357, 1227, 1135 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.63-7.55 (2H, m), 7.52-7.46 (4H, m), 7.36-7.29 (1H, m), 7.25-7.12 (4H, m), 6.94-6.91 (2H, m), 4.36 (2H, s); ¹³C NMR (75 MHz, CDCl3)

: 144.0, 139.7, 136.1, 129.5, 128.5, 126.7, 126.1, 126.0, 124.9, 124.1, 123.5, 122.6, 120.0, 119.3, 116.3, 110.5, 25.8; ESI-HRMS m/z: calcd for C19H16NS [M + H]⁺ 290.0998, found 290.0994.

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第１３節 第３章第４節第１項の実験

(2E, 4E)-4-[2-(4-Methoxyphenyl)hydrazono]-4-methyl-2-butenoic Acid Methyl Ester (31) [Scheme 73]. To a solution of (2E)-4-oxo-2-pentenoic acid methyl ester (1.0 g, 7.8 mmol) in pyridine (20 mL) was added p-methoxyphenylhydrazine hydrochloride (1.63 g, 9.4 mmol) at room temperature. After being stirred for 0.5 h, the reaction mixture was acidified with 10% HCl and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by recrystallization (hexane/AcOEt) to afford 31 (1.92 g, 99%) as yellow solid. Mp: 153-155 °C (hexane-AcOEt); IR (KBr): 3319, 1682 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.57 (1H, br s), 7.51 (1H, d, J = 16.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 5.98 (1H, d, J = 16.0 Hz), 3.79 (3H, s), 3.78 (3H, s), 1.97 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 167.7, 154.7, 145.7, 138.7, 137.6, 116.3, 114.7, 55.6, 51.6, 9.8; ESI-HRMS m/z: calcd for C13H17O3N2 [M + H]⁺ 249.1234, found 249.1232.

5-Methoxy-2-methyl-1H-indole-3-acetic Acid Methyl Ester (32) ⁷⁸⁾ [Scheme 73]. To a solution of 31 (1.0 g, 4.0 mmol) in MeCN (40 mL) was added tBuI (1.43 mL, 12.1 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 2 : 1) to afford 32 (883.5 mg, 95%) as yellow oil. IR (neat): 3397, 1733 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.76 (1H, br s), 7.15 (1H, dd, J = 9.0, 0.5 Hz), 6.99 (1H, d, J = 2.5 Hz), 6.77 (1H, dd, J = 9.0, 2.5 Hz), 3.86 (3H, s), 3.67 (3H, s), 3.66 (2H, s), 2.39 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 172.5, 154.1, 133.5, 130.0, 128.9, 110.9, 104.3, 100.3, 55.9, 51.9, 30.3, 11.8; ESI-HRMS m/z: calcd for C13H16O3N [M + H]⁺ 234.1125, found 234.1123.

1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid Methyl Ester (148) ⁸⁰⁾ [Scheme 73]. To a solution of 32 (883.5 mg, 3.79 mmol) in CH2Cl2 (35 mL) was added Et3N (2.63 mL, 19.0 mmol), DMAP (232 mg, 1.90 mmol) and p-chlorobenzoyl chloride (0.58 mL, 4.55 mmol) at reflux. After being stirred for 24 h, the reaction mixture was cooled to room temperature, diluted with 10% HCl solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) to afford 148 (1.25 g, 89%) as pale yellow solid. Mp:

162-163 °C (hexane-AcOEt); IR (KBr): 1733, 1672 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.66 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5 Hz), 6.96 (1H, d, J = 2.5 Hz), 6.86 (1H, d, J = 9.0 Hz), 6.67 (1H, dd, J = 9.0, 2.5 Hz), 3.83 (3H, s), 3.70 (3H, s), 3.67 (2H, s), 2.38 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 171.3, 168.2, 156.0, 139.2, 135.9, 133.8, 131.1, 130.7, 130.6, 129.1, 114.9, 112.5, 111.5,

117

101.2, 55.7, 52.1, 30.1, 13.3; ESI-HRMS m/z: calcd for C20H19O4N³⁵Cl [M + H]⁺ 372.0997, found 372.0995.

1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid (Indomethacin) ⁷⁷⁾ [Scheme 73]. To a solution of 148 (1.25 g, 3.36 mmol) in pyridine (40 mL) was added LiI (9.0 g, 67.2 mmol) at reflux. After being stirred for 20 h, the reaction mixture was cooled to 0 °C, diluted with 10%

HCl solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 1 : 3 then AcOEt) to afford Indomethacin (1.01 g, 84%) as pale yellow solid. Mp:

159-161 °C (AcOEt); IR (KBr): 1733, 1672 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.66 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5 Hz), 6.95 (1H, d, J = 2.5 Hz), 6.85 (1H, d, J = 9.0 Hz), 6.67 (1H, dd, J

= 9.0, 2.5 Hz), 3.83 (3H, s), 3.69 (2H, s), 2.39 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 176.2, 168.3, 156.0, 139.3, 136.2, 133.8, 131.2, 130.7, 130.4, 129.1, 115.0, 111.8, 111.7, 101.2, 55.7, 29.9, 13.3;

ESI-HRMS m/z: calcd for C19H17O4N³⁵Cl [M + H]⁺ 358.0841, found 358.0838.

118

第１４節 第３章第４節第２項の実験

(2E, 4E)-4-[2-(4-Methoxyphenyl)hydrazono]-3-methyl-2-butenoic Acid Ethyl Ester (33) [Scheme 75]. To a solution of 3-methyl-4-oxo-butenoic acid ethyl ester ⁸³⁾ (859 mg, 6.0 mmol) in pyridine (20 mL) was added p-methoxyphenylhydrazine hydrochloride (1.16 g, 6.6 mmol) at room temperature. After being stirred for 0.5 h, the reaction mixture was diluted with H2O and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane : AcOEt = 3 : 1) to afford 33 (1.37 g, 87%) as yellow solid. Mp: 115-117 °C (hexane-AcOEt); IR (KBr): 3276, 1675 cm^-1; ¹H NMR (300 MHz, CDCl3) : 7.82 (1H, br s), 7.31 (1H, s), 7.02 (2H, d, J

= 9.0 Hz), 6.85 (2H, d, J = 9.0 Hz), 5.79 (1H, s), 4.20 (2H, q, J = 7.0 Hz), 3.78 (3H, s), 2.44 (3H, d, 1.0 Hz), 1.30 (3H, t, J = 7.0 Hz); ¹³C NMR (75 MHz, CDCl3) : 167.0, 154.4, 151.7, 138.5, 137.7, 118.7, 114.8, 114.1, 59.8, 55.6, 14.3, 13.3; ESI-HRMS m/z: calcd for C14H19O3N2 [M + H]⁺ 263.1390, found 263.1389.

3,3a,8,8a-Tetrahydro-5-methoxy-1,3a-dimethyl-pyrrolo[2,3-b]indol-2(1H)-one (35) [Scheme 75]. To a solution of 33 (52 mg, 0.2 mmol) in MeCN (2 mL) was added tBuI (71 μL, 0.6 mmol) at reflux. After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in EtOH (1 mL). To this solution was added methyl amine (33 wt% in EtOH, 1 mL) at room temperature. After being stirred for 24 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by PTLC (AcOEt) to afford 35 (23.0 mg, 50%) as pale yellow oil. IR (neat): 3318, 1677 cm^-1; ¹H NMR (300 MHz, CDCl3) : 6.70-6.61 (3H, m), 4.88 (1H, s), 4.30 (1H, br s), 3.76 (3H, s), 2.85 (3H, s), 2.79 (1H, d, J = 17.0 Hz), 2.60 (1H, d, J = 17.0 Hz), 1.45 (3H, s); ¹³C NMR (75 MHz, CDCl3) :

172.5, 154.8, 140.5, 137.9, 113.6, 112.1, 109.6, 85.1, 55.9, 47.7, 44.0, 26.8, 26.0; ESI-HRMS m/z:

calcd for C13H17O2N2 [M + H]⁺ 233.1285, found 233.1282.

3,3a,8,8a-Tetrahydro-5-methoxy-3a-methyl-2H-furo[2,3-b]indol-2-one (36) ⁸⁴⁾ [Scheme 75]. To a solution of 33 (52 mg, 0.2 mmol) in MeCN (2 mL) was added tBuI (71 μL, 0.6 mmol) at reflux.

After being stirred for 0.5 h, the reaction mixture was quenched with 10% Na2S2O3 solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in EtOH (5 mL). To this solution was added 6M NaOH solution (1.5 mL) at room temperature. After being stirred for 4.5 h, the reaction mixture was diluted with saturated NH4Cl solution and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC

119

(hexane : AcOEt = 1 : 1) to afford 36 (22.4 mg, 52%) as pale yellow oil. IR (neat): 3384, 1762 cm^-1;

1H NMR (300 MHz, CDCl3) : 6.71-6.68 (2H, m), 6.62 (1H, dd, J = 7.5, 2.0 Hz), 5.67 (1H, s), 4.81 (1H, br s), 3.76 (3H, s), 2.98 (1H, d, J = 18.0 Hz), 2.81 (1H, d, J = 18.0 Hz), 1.47 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 174.7, 154.6, 139.7, 134.1, 113.8, 110.5, 110.0, 101.0, 55.9, 50.4, 41.9, 23.5;

ESI-HRMS m/z: calcd for C12H14O3N [M + H]⁺ 220.0968, found 220.0969.

3,3a,8,8a-Tetrahydro-5-methoxy-1,3a,8-trimethyl-pyrrolo[2,3-b]indol-2(1H)-one (153) ⁸⁶⁾ [Scheme 76]. To a solution of 35 (20 mg, 0.09 mmol), 37% aqueous HCHO (46 μL, 0.44 mmol) and AcOH (25 μL, 0.44 mmol) in MeCN (1.5 mL) was added NaBH3CN (21.6 mg, 0.34 mmol) at 0 °C. After being stirred for 5 min, the reaction mixture was quenched with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (AcOEt) to afford 153 (21.0 mg, 99%) as yellow oil. IR (neat):

1689 cm^-1; ¹H NMR (300 MHz, CDCl3) : 6.71 (1H, dd, J = 8.5, 2.5 Hz), 6.67 (1H, d, J = 2.5 Hz), 6.43 (1H, d, J = 8.5 Hz), 4.56 (1H, s), 3.75 (3H, s), 3.02 (3H, s), 2.95 (3H, s), 2.74 (1H, d, J = 17.5 Hz), 2.53 (1H, d, J = 17.5 Hz), 1.45 (3H, s); ¹³C NMR (75 MHz, CDCl3) : 173.1, 153.7, 143.7, 137.0, 113.1, 109.9, 108.7, 93.3, 56.0, 46.0, 44.1, 37.3, 28.4, 26.8; ESI-HRMS m/z: calcd for C14H19O2N2 [M + H]⁺ 247.1441, found 247.1435.

1,2,3,3a,8,8a-Hexahydro-5-methoxy-1,3a,8-trimethyl-pyrrolo[2,3-b]indole (Esermethole) ^{9e, 86)} [Scheme 76]. To a solution of 153 (20 mg, 0.08 mmol) in THF (2 mL) was added a suspension of LiAlH4 (30.8 mg, 0.81 mmol) in THF (2 mL) at 0 °C. After being stirred at reflux for 2 h, the reaction mixture was cooled to 0 °C and quenched with AcOEt. Then, it was diluted with H2O and extracted with AcOEt. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by PTLC (CHCl3 : MeOH = 10 : 1) to afford Esermethole (14.5 mg, 78%) as pale yellow oil. IR (neat): 2956, 2930, 2864, 1596, 1498, 1280, 1221, 1122, 1033 cm^-1; ¹H NMR (300 MHz, CDCl3) : 6.68 (2H, m), 6.37 (1H, d, J = 8.0 Hz), 4.11 (1H, s), 3.75 (3H, s), 2.90 (3H, s), 2.81-2.74 (1H, m), 2.67-2.59 (1H, m), 2.45 (3H, s), 2.00-1.95 (2H, m), 1.44 (3H, s);

13C NMR (75 MHz, CDCl3) : 153.0, 146.4, 138.1, 112.2, 109.7, 107.6, 98.0, 56.0, 53.1, 52.8, 40.6, 38.1, 37.8, 27.3; ESI-HRMS m/z: calcd for C14H21ON2 [M + H]⁺ 233.1648, found 233.1642.

120

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